Quantitative analysis of polymorphic mixtures of carbamazepine by Raman spectroscopy and principal components analysis

Abstract

The polymorphic behaviour of drugs is a major concern of the pharmaceutical industry as it may have considerable formulation, therapeutic, legal and commercial implications. It is therefore crucial to be able adequately to identify and quantify different polymorphic forms of drugs as early as possible in the drug discovery and development process. The aim of the present study was to investigate the application of Raman spectroscopy and principal components analysis (PCA) to the quantitative analysis of polymorphic mixtures of carbamazepine forms III and I, based on both individual peak areas and heights in the Raman spectra and whole wavenumber ranges. Various linear regressions indicated that in general using every fourth wavenumber value of a larger region of the Raman spectrum gives better quantitative results than choosing defined peak areas and peak heights, as the spectral differences between the polymorphs were only subtle. Baseline correction of the spectral data did not appear to improve the quantitative analysis, with detection and quantification limits being the lowest (0.33 and 1.09%, respectively) and R 2 being the highest (0.96) when using every fourth wavenumber value from 2950 to 3100 cm −1 as input data for the PCA analysis without baseline correction. This study demonstrated that PCA of Raman spectroscopic data provides a sensitive method for the quantitative analysis of polymorphic forms, with a quantitation limit of <2%, if the spectral input data are selected carefully. In the absence of clear and distinct spectral differences at certain wavenumbers between the polymorphic forms, selection of larger spectral regions that contain most of the detectable differences between the two forms appears to be the best data selection technique.

Quantitative analysis of paracetamol polymorphs in powder mixtures by FT-Raman spectroscopy and PLS regression

“…The FT-Raman method of Al Zoubi et al [8] utilizes the 454-465 cm −1 pair of bands, which are partially overlapping, and it requires peak deconvolution [8], which is a rather elaborate procedure, for routine analysis tasks. Furthermore, univariate methods lack the advantages of modern multivariate calibration algorithms, which have been proven highly efficient in the quantitation of polymorphs in powder mixtures [10,13]. Therefore, in the present study, it was considered important to develop a simple FT-Raman method for the quantitative analysis of binary mixtures of paracetamol crystal forms I and II, taking full advantage of the high efficiency of modern multivariate calibration methods.…”

“…FT-Raman spectroscopy in particular, is well-suited for the identification and quantitative analysis of crystal polymorphs [6], since it requires very little sample preparation, thus minimizing the risk of solid-state transformations of metastable polymorphs, while the particle size and shape of the sample have little effect [7]. The potential of Raman techniques in the quantitative analysis of polymorphs has been demonstrated in the case of powder mixtures [7][8][9][10], as well as drug products [6,11]. A spectroscopic FTIR as well as an FT-Raman method for the quantitative analysis of paracetamol polymorphs I and II in powder mixtures has been developed by Al Zoubi et al [8] by the use of univariate classical least squares regression.…”

Measurement of lactose crystallinity using Raman spectroscopy

“…RS has already been applied to the identification and characterisation of the polymorphic forms of pharmaceutical actives [13][14][15][16][17]. Through the measurement of the wavelength and intensity of inelastically scattered light from molecules, RS probes the molecular and crystal lattice vibrations and is therefore sensitive to the composition, bonding, chemical environment, phase, and crystalline structure of the material [18].…”

Determination of the relative amounts of three crystal forms of a benzimidazole drug in complex finished formulations by FT-Raman spectroscopy

“…Some recent overview articles summarize the current status of Raman spectroscopy with emphasis on the pharmaceutical applications [8][9][10][11][12]: most of the Raman research has however focused on the chemical and solid-state characterization of the pure chemical compounds, e.g. [13][14][15][16], and only rarely on the quantification of the solid-states of the drug substances formulated in a finished drug product, e.g. [17][18][19].…”